For monomers with different reactivity ratios, the faster reacting monomer reacts to form a homopolymer block with some possible incorporation of the slower reacting comonomer. Thus, the structure of the polymer depends on the reaction rates of the monomers. Consequently, the slower reacting monomer is not fully incorporated into the copolymer structure and remains as unreacted product. Any unreacted product necessitates drying for removal which can cause premature degradation of the copolymer and/or cause poor process performance in subsequent steps. Furthermore, the addition reaction is exothermic which increases reaction temperatures, impacting the polymerization rate of the co-monomers, causing degradation, and impacting control of the molecular weight and scale-up capabilities. In some instances, the slow reacting monomer either has low solubility in the resulting polymer, resulting in two phases, or is never incorporated. Thus, the possible range of the final composition is limited.
Traditional methods of polymerizations are to add the co-monomers to the reactor with the slow reacting monomer added in excess to achieve the final composition. To increase incorporation of the slow reacting monomer and to achieve a random structure the reaction time is extended. This extended time does not give full conversion of the slow reacting monomer and causes degradation of the polymer. Also, the structure is not controlled to achieve different sequences of the monomers.
Blocky polymeric structures are known to be formed by sequentially adding monomers to the reaction vessel over a period of time. Examples of such polymers are Monocryl™, available from Ethicon Corporation, Somerville, N.J. and Maxon™, and Biosyn™, available from Tyco International. In conventional processes used to form bioadsorbable copolymers, one or more monomers are added to the reactor and polymerized. If it is two monomers, the reaction time must be extended to achieve incorporation and randomization. After this time, additional monomer is added to achieve a block segment of this monomer. With this approach, the structure is controlled by reaction rates of the monomers and transesterification, resulting in either a random or block polymer structure.
Methods to improve incorporations of slower reacting monomers with low solubility have not been previously proposed. European Patent No. 098,394 B1 to Casey, et al. (“Casey”) mentions that feeding the two monomers (glycolide and trimethylene carbonate) to the reactor in proportion to their reactivity ratios can control the structure of the middle block. However, there is no mention of adjusting the feed rates due to the effects of the changing reactant compositions formed as the reaction proceeds. Casey also fails to provide exemplification or to mention how the monomer feed rates are selected. Casey also is silent as to issues involving decreased solubility of the reactants in the polymer formed, incorporation of the slower reacting monomer and adjustment of the rate of incorporation of the slower monomer in varying the copolymer structure.
Methods of preparing bioadsorbable block polymers have also been proposed. For example, U.S. Pat. No. 4,605,730 to Shalaby et al. describes a two step polymerization method. The first step produces a low molecular weight prepolymer of ε-caprolactone and glycolide. This prepolymer contains more than 60% ε-caprolactone. Once the prepolymer is formed, in the second step, additional glycolide or glycolide/ε-caprolactone is added to the prepolymer, and the resultant mixture is further polymerized.
U.S. Pat. No. 4,700,704 describes surgical sutures made from polymeric materials comprising from about 20 to about 35 weight % ε-caprolactone and from about 65 to about 80 weight % glycolide based sequences. This patent also describes a two step polymerization method. The first step produces copolymers by initially forming a low molecular weight prepolymer of ε-caprolactone and glycolide. This prepolymer contains more than 50 percent ε-caprolactone. Once the prepolymer is formed, in the second step, additional glycolide or glycolide/ε-caprolactone is added to the prepolymer, and the resultant mixture is further polymerized.
U.S. Pat. No. 5,133,739 to Bezwada et al. (“Bezwada”) discusses the preparation of an ε-caprolactone/glycolide copolymer, which is the reaction product of a high molecular weight prepolymer of ε-caprolactone and glycolide, and the balance glycolide. However, Bezwada recognizes that there are problems associated with the copolymers where the mole ratio of ε-caprolactone to glycolide is above 45:55. This includes that the solubility of the prepolymer in the glycolide monomer and its compatibility with the developing hard polyglycolide block would not be adequate to prepare a single phase copolymer with the most desirable properties.
Therefore, there is a need for a method of preparing a bioadsorbable copolymer that incorporates a faster reacting monomer and a slower reacting monomer, which allows control over the structure of the copolymer, including the preparation of a block polymer, while maintaining solubility of the monomer in thus formed polymer and preventing premature degradation of the resultant copolymer.